Percutaneously Absorbable Preparation, Percutaneously Absorbable Preparation Holding Sheet, and Percutaneously Absorbable Preparation Holding Equipment

ABSTRACT

Self-dissolving needle-like or filamentous shape percutaneously absorbable preparations, by which inherently poorly absorbable drugs into the body through the skin is efficiently administered. The preparations are made of at least one material selected from the group consisting of proteins, polysaccharides, polyvinyl alcohols, carboxyvinyl polymers and sodium polyacrylic acids. An active substance contained therein is released in a sustained-release fashion (1) by forming a water-insoluble layer on its surface, (2) by holding the active substance in porous materials, or (3) by imparting a long-acting characteristic to the active substance. The present invention also provides a sheet-like carrier for holding the preparations on at least one of the sides thereof, and a piece of equipment for holding the preparations so as to facilitate the administration of them.

TECHNICAL FIELD

The present invention relates to percutaneously absorbable preparationsper se, a sheet-like carrier for holding the preparations, and a pieceof equipment for holding the preparations. More particularly, it relatesto (1) a self-dissolving percutaneously absorbable preparation having aslender, pointed shape adapted for insertion into the skin, this shapebeing hereinafter referred to as “needle-like or filamentous shape”, thepreparations which include a base holding an active substance ofproteins and polysaccharides etc., (2) a sheet-like carrier for holdingthe percutaneously absorbable preparations on at least one of the sidesthereof, and (3) a piece of equipment for holding the preparations in apenetration hole formed in its main body. In this specification, theterm “preparations” in plural means not only a product but alsoproducts, so as to distinguish from “preparation” in singular meaningthe act of preparing.

BACKGROUND ART

As one of the noninvasive methods for the administration of drugs, adrug is administered with the use of percutaneously absorbablepreparations. For instance, percutaneously absorbable preparations suchas ointment, cream, lotion, poultice and patch have been used. The useof these percutaneous preparations is usually limited to the localtherapy of disease localized on the skin. Because of the barrierfunction possessed by the skin, the systemic therapy with drugs throughthe percutaneous route is difficult due to the low systemic availabilityof locally applied drugs to the skin. Though several patch typeTransdermal Therapeutic Systems (TTS) have been launched onto themarket, the drugs are limited to estrogen, nitric acid derivatives,tulobuterol and nicotine etc. that show their pharmacological activitiesat low plasma or serum concentration, i.e., their therapeuticconcentrations are lower than 20 ng/mL. So far, the absorption ofmacromolecular drugs such as insulin through percutaneous route isdifficult because of their low skin permeability and no percutaneouspreparations have been developed up to now. Therefore, macromoleculardrugs are still administered to patients by injections.

Under such a background, development of injection technology with lowinvasion has been challenged and microneedle was developed as one ofthose technologies. Microneedle is a fine needle having no pain when isapplied onto the skin. As microneedle material, not only steel as aconventional injection needle but also silicon etc, are used (Non-patentdocuments 1 and 2). These microneedles have holes in themselves asconventional injection needles and drug solutions are injected throughthese holes. In addition, self-dissolving microneedle made of basematerial dissolving in the body was also developed. Active substance iscontained in the base and is released from microneedle by thedissolution of the base after inserted into the skin. For instance, aself-dissolving microneedle made of maltose as the base is disclosed(Patent document 1). In addition, the self-dissolving microneedles madeof polylactic acid, polyglycolic acid or poly-ε-caprolactone are alsoknown.

In addition, when the active substance is a drug that receives highclearance from the systemic circulation such as insulin, long-termpharmacological activity is needed. In such a case, self-dissolvingmicroneedle having the function of sustained-release characteristics ofthe active substance is required. For instance, a self-dissolvingmicroneedle consisting of polylactic acid has a sustained-releasefunction of the active substance.

Patent document 1: JP2003-238347 A

Non-patent document 1: D. K. Armini and C. Lui, “Microfabricationtechnology for polycaprolactone, a biodegradable polymer”, Journal ofMicromechanics and Microengineering, 2000, 10, 80-84

Non-patent document 2: M. R. Prausnitz, “Microneedles for transdermaldrug delivery”, Advanced Drug Delivery Reviews, 2004, 56, 581-587

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

When a self-dissolving microneedle which has a base consisting ofmaltose is prepared, an active substance is added to the melt maltoseheated to more than the melting point of maltose and thereafter themixture is molded. Here, the melting point of maltose is high, about102-103° C. In a microneedle which has a base consisting of maltose, anactive substance to be held in the base is therefore exposed to a hightemperature during its manufacturing process. However, there are manyactive substances that receive degradation, denaturation or inactivationat a high temperature. A self-dissolving microneedle of which base ismaltose is therefore difficult to contain these active substances.Especially, when the active substances are peptides and proteins whichcan escape neither denaturation nor inactivation by heating, it isextremely difficult to use maltose as a base. When an active substanceis insulin, denaturation and inactivation by high temperature isprevented in some degree by using insulin powder. However, since moldedmaltose in which powder is dispersed is fragile, a microneedlecontaining maltose as a base and insulin powder held therein isdifficult to keep its physical strength. Further, since maltose has astrong hygroscopicity, a self-dissolving microneedle which has a baseconsisting of maltose adsorbs moisture as the time passes and the top ofthe microneedle becomes soft. As a result, it has a pitfall, i.e.unavailability for the insertion into the skin. Therefore, it may bedifficult for a self-dissolving microneedle containing maltose as a baseto administer an active substance quantitatively.

Still further, when polylactic acid, a water-insoluble polymer, is usedas a base for a microneedle to obtain sustained-release characteristicsof the active substance, polylactic acid needs to be dissolved with anorganic solvent such as methylene chloride. However, some activesubstances receive denaturation or inactivation by exposure to organicsolvents. For instance, when proteins or peptides such as insulin areemployed as an active substance, they are easily denaturated orinactivated by exposure to an organic solvent. Therefore, aself-dissolving microneedle which has a base consisting of awater-soluble material and has sustained-release characteristics isdesired.

The primary object of the present invention is to provide a needle-likeor filamentous shape self-dissolving percutaneously absorbablepreparation, hereinafter being sometimes referred to merely as“preparations”, having suitable physical strength for the percutaneousdelivery of poorly absorbable drugs through a percutaneous route byproducing at relatively low temperature without the use of any organicsolvent.

Means to Solve the Problems

To solve the above mentioned problems, the inventor has succeeded toinvent needle-like or filamentous shape self-dissolving percutaneouslyabsorbable preparations that are prepared in room or under lowtemperature conditions through many studies concerning the screening ofthe base materials. The inventor has also succeeded to inventneedle-like or filamentous shape self-dissolving percutaneouslyabsorbable preparations having sustained-release characteristics ofactive substance without polylactic acid. In addition, the inventor hassucceeded in preparing the percutaneously absorbable preparationsholding sheet-like carrier by which the percutaneously absorbablepreparations are administered percutaneously with high efficiency.Furthermore, the inventor has completed this invention by preparingpercutaneously absorbable preparations holding equipment by whichneedle-like or filamentous shape percutaneously absorbable preparationsare inserted into the skin with ease. The present invention will bedescribed hereinafter.

According to a first aspect of percutaneously absorbable preparations ofthe present invention, percutaneously absorbable preparations having abase of water-soluble and biologically soluble polymer material, and anactive substance held in the base are characterized by having a slender,pointed shape, such as a needle-like or filamentous shape, adapted forinsertion into skin to percutaneously administer the active substanceinto the body, wherein the polymer material is at least one materialselected from the group consisting of proteins, polysaccharides,polyvinyl alcohols, carboxyvinyl polymers and sodium polyacrylic acids.

The percutaneously absorbable preparations in this aspect are aself-dissolving percutaneously absorbable type by which the activesubstance is administered percutaneously into the body by inserting thepreparations into the skin, wherein the active substance is held in thewater-soluble and biologically soluble macromolecular base. In thepercutaneously absorbable preparations in this aspect, the base is madeof at least one material selected from the group consisting of proteins,polysaccharides, polyvinyl alcohols, carboxyvinyl polymers and sodiumpolyacrylic acids, and the preparations have a needle-like or afilamentous shape. The percutaneously absorbable preparations in thisaspect can be made at room temperature or at relatively low temperature,because the base consists of protein etc. Therefore, the activesubstance can be kept from exposure to high temperature during themanufacturing process. More specifically, though the active substance isinherently unstable at high temperature, it remains active during themanufacturing process. As a result, the active substance is highlyefficiently administered percutaneously to the body by use of thepercutaneously absorbable preparations in this aspect.

Proteins, polysaccharides, polyvinyl alcohols, carboxyvinyl polymers andsodium polyacrylic acids that are used as a base of the percutaneouslyabsorbable preparations in this aspect belong to “thread-formingsubstance” that becomes glue when dissolved in a small amount of water.

According to a second aspect of percutaneously absorbable preparationsof the present invention, percutaneously absorbable preparations havinga base of water-soluble and biologically soluble polymer material, andan active substance held in the base, are characterized by having aslender, pointed shape, such as a needle-like or filamentous shape,adapted for insertion into skin to percutaneously administer the activesubstance into the body, wherein the percutaneously absorbablepreparations have a water-insoluble layer formed on the surface thereof,and wherein the active substance is released in a sustained-releasefashion.

The advantage of the percutaneously absorbable preparations in thisaspect is in the capability of sustained-releasing the active substance.More specifically, the percutaneously absorbable preparations have awater-soluble and biologically soluble macromolecular base and an activesubstance held in the base. The active substance is percutaneouslyadministered into the body, wherein the preparation is provided with awater-insoluble layer formed on its surface. In the percutaneouslyabsorbable preparations in this aspect, no organic solvent is usedduring the manufacturing process of the base, because the base consistsof water-soluble materials. More specifically, since the activesubstance held in the base is not exposed to organic solvent, the activesubstance potentially keeps its activity during the manufacturingprocess. As a result, the active substance is percutaneouslyadministered to the body highly efficiently by the percutaneouslyabsorbable preparations in this aspect. In addition, the percutaneouslyabsorbable preparations in this aspect are easily manufactured as theactive substance has sustained-release characteristics by forming awater-insoluble layer on its surface.

Preferably, the water-insoluble layer is formed by cross-reaction.

The percutaneously absorbable preparations of the preferred aspect areeasily manufactured.

According to a third aspect of percutaneously absorbable preparations ofthe present invention, percutaneously absorbable preparations having abase of water-soluble and biologically soluble polymer material, and anactive substance held in the base, are characterized by having aslender, pointed shape, such as a needle-like or filamentous shape,adapted for insertion into skin to percutaneously administer the activesubstance into the body; wherein the base contains a porous compound,and wherein the active substance is held in the porous compound and isreleased in a sustained-release fashion.

Preferably, the porous material is at least one material selected fromthe group consisting of calcium silicate, aluminum silicate, magnesiumsilicate, anhydrous silicate, porous calcium carbonate, porous calciumphosphate and porous silicon.

The percutaneously absorbable preparations in this aspect areneedle-like or filamentous shape self-dissolving percutaneouslyabsorbable preparations having a sustained-release function of theactive substance. More specifically, the percutaneously absorbablepreparations have a water-soluble and biologically solublemacromolecular base and an active substance held in the base and theactive substance is percutaneously administered into the body, whereinthe active substance is held in porous materials contained in the base.In the percutaneously absorbable preparations in this aspect, no organicsolvent is used during the manufacturing process of the base, becausethe base consists of water-soluble materials. More specifically, sincethe active substance held in the base is kept from exposure to organicsolvent, the active substance remains active during the manufacturingprocess. As a result, the active substance is administeredpercutaneously into the body highly efficiently by the percutaneouslyabsorbable preparations in this aspect. In addition, the percutaneouslyabsorbable preparations in this aspect do not need a special treatmentto allow the active substance to possess sustained-releasecharacteristics, because the active substance is held in porousmaterials contained in the base.

According to a fourth aspect of percutaneously absorbable preparationsof the present invention, percutaneously absorbable preparations havinga base of water-soluble and biologically soluble polymer material, andan active substance held in the base, is characterized by having aslender, pointed shape, such as a needle-like or filamentous shape,adapted for insertion into skin to percutaneously administer the activesubstance into the body, wherein the active substance is a long-actingmaterial and is released in a sustained-release fashion.

Preferably, the long-acting substance is long-acting type insulin orprotein cross-linked with polyethylene glycol.

The percutaneously absorbable preparations in this aspect havesustained-release characteristics of active substances. Morespecifically, the percutaneously absorbable preparations have awater-soluble biologically soluble macromolecular base and an activesubstance held in the base, and the active substance is percutaneouslyadministered into the body, wherein the active substance is along-acting substance. No organic solvent is used to prepare the base inthe percutaneously absorbable preparations, because the base consists ofa water-soluble substance. More specifically, the active substanceremains active during the manufacturing process, since the activesubstance held in the base is kept from exposure to the organic solvent.As a result, the active substance is highly efficiently absorbed throughthe skin. Furthermore, no special treatment is needed to obtain thesustained-release characteristics of the active substance, since along-acting substance is used as the active substance. Examples of thelong-acting substance include long-acting insulin and polyethyleneglycol complexed proteins.

Preferably, the polymer material is at least one material selected fromthe group consisting of proteins, polysaccharides, polyvinyl alcohols,carboxyvinyl polymers and sodium polyacrylic acids.

The percutaneously absorbable preparations in this preferred aspect isprepared at room temperature or at relatively low temperature, becausethe base is made of protein etc. Therefore, the active substance held onthe base is kept from exposure to high temperature during themanufacturing process. More specifically, though the active substance isinherently unstable at high temperature, it does not loss the activityduring manufacturing process. As a result, the active substance ishighly efficiently administered percutaneously into the body by thepercutaneously absorbable preparations.

Preferably, the protein is at least one material selected from the groupconsisting of serum albumin, serum α-acid glycoprotein and gelatin.

Preferably, the polysaccharide is at least one material selected fromthe group consisting of glycogen, dextrin, dextran, dextran sulfate,sodium chondroitin sulfate, hydroxy propyl cellulose, alginic acid,agarose, chitin, chitosan, pullulan and hyaluronic acid.

The percutaneously absorbable preparations in these preferred aspectsensure hygienic safety, because the base is made of pharmaceuticalpreparations whose safety is generally acknowledged.

Preferably, the base contains an absorption rate controller forcontrolling the absorption rate of the active substance.

Preferably, the absorption rate controller is an absorption enhancer.

Preferably, the absorption enhancer is a surfactant.

In such preferred aspects, the dissolution rate and permeability of theactive substance is accelerated by the action of surfactant even whenthe active substance has a low solubility and a low permeability in theepidermis and dermis of the skin. As a result, the active substance iseffectively percutaneously administered into the body.

Preferably, the base contains a thread-reducing agent, thereby reducingthe thread-forming property thereof.

Preferably, the thread-reducing agent is polyethylene glycol orL-glutamic acid L-lysine.

According to the preferred aspects, the thread-forming property of thebase is reduced. Since the thread-forming property of the base is wellcontrolled, the preparations are smoothly manufactured.

Preferably, the active substance is a drug.

The use of the drug-base percutaneously absorbable preparations ensuresthat the active substance is effectively administered percutaneouslyinto the body for the therapy, prophylaxis and diagnosis of disease.

Preferably, the drug falls in peptides, proteins, nucleic acids,polysaccharides or vaccine.

According to the preferred aspect, percutaneously poorly absorbabledrugs like peptides, proteins, nucleic acids, polysaccharides andvaccine are administered percutaneously into the body.

Preferably, the base contains a stabilizer for stabilizing the activesubstance.

In this case, the active substance held in the base is stabilized by theaction of the stabilizer. As a result, a possible inactivation or anyother inadequacy of the active substance is eliminated. When the activesubstance is peptides or proteins, a protease inhibitor and a nucleaseinhibitor are desirably used for peptides/proteins and nucleic acids,respectively.

Preferably, the preparations further include a moisture-proof layerformed on the surface thereof.

Thus, the percutaneously absorbable preparation can have a reducedhygroscopicity because of the existence of the moisture-proof layer onits surface. As a result, the top of the preparations is prevented fromsoftening, and the percutaneously absorbable preparations are insertedinto the skin. The active substance is administered exactly to a desiredquantity.

Preferably, the preparations are constricted or have a secant in part onthe surface thereof.

The percutaneously absorbable preparations in this preferred aspect areconstricted or have a secant on the part or parts of their surface, andare cut along the constricted portion or the secant after thepreparations are inserted into the skin. As a result, the part or partsof the preparations, from the secant to the top, are inserted into theskin and the active substance is accurately dosed.

According to a fifth aspect of percutaneously absorbable preparations ofthe present invention, the percutaneously absorbable preparations arecharacterized in at least two of the preparations of any one of theabove-described aspects linked in series.

According to this aspect, the linked series of preparations aresequentially administered into the body through the skin.

According to an aspect of a sheet-like carrier of the present invention,there is provided a sheet-like carrier for holding at least one of thepercutaneously absorbable preparations on at least one of the surfacesthereof, wherein the preparations held on the carrier are inserted intothe skin by pushing the carrier thereonto.

The present aspect is directed to a sheet-like carrier for holding thepercutaneously absorbable preparations, wherein at least one of thepercutaneously absorbable preparations except the fifth aspect are heldon the sheet-like carrier and the percutaneously absorbable preparationsare inserted into the skin by pressing the sheet-like carrier onto theskin. As a result, the percutaneously absorbable preparations held onthe sheet-like carrier are inserted into the skin. According to thisaspect, the percutaneously absorbable preparations are highlyefficiently administered.

According to an aspect of equipment of the present invention, there isprovided a piece of equipment for holding percutaneously absorbablepreparations including having a base of water-soluble and biologicallysoluble polymer material, an active substance held in the base, andhaving a slender, pointed shape, such as a needle-like or filamentousshape, adapted for insertion into skin to percutaneously administer theactive substance into the body, the equipment including a main bodyhaving a penetration hole in and along which the preparations are moved.

According to another aspect of equipment of the present invention, thereis provided a piece of equipment for holding percutaneously absorbablepreparations, the equipment including a main body having a penetrationhole in and along which the preparations are moved, wherein thepreparations fall in any one of the above-described aspects.

In the equipment in these aspects, the percutaneously absorbablepreparations move in and along the penetration hole, and are insertedinto the skin by pushing out the preparations from the other end of thepenetration hole. As a result, the preparations are accurately andeasily inserted into the skin.

Preferably, the penetration hole accommodates a spacer kept in contactwith the preparations held in the penetration hole, so that the spacermoves in and along the penetration hole while being kept in contact withthe preparations.

When the preparations held in the penetration hole are pushed to theskin, a pushing unit is inserted into the hole to push it out from theother end of the hole. At the time when the percutaneously absorbablepreparations are completely inserted into the skin, the pushing unitcomes into contact with the skin. However, a small amount of the bodyfluid may leak on the skin at a spot where the preparations areinserted, and the body fluid may adhere to the pushing unit. Morespecifically, when several pieces of equipment are used one afteranother as if they are cartridges, the patients are in danger of beinginfected through the body fluid. The equipment in the preferred aspecthas a spacer, which is kept in contact with the percutaneouslyabsorbable preparations in the penetration hole. The spacer moves in andalong the penetration hole. By use of this equipment, the percutaneouslyabsorbable preparations are pushed via the spacer by a pushing unit. Asa result, the pushing unit does not come into contact with the skin atthe point when the preparations are completely inserted into the skin.Therefore, by use of the equipment, there is no fear of infectionthrough the body fluid among the patients even if a plurality ofequipment are used one after another as if they are cartridges.

Preferably, the main body includes a concave to which the penetrationhole is open.

Owing to the presence of the concave, the preparations are easilyreleased under the pushing urge. In addition, the concave makes it easyto attach the pushing unit to the equipment.

Preferably, the concave includes female threads cut on the inside wallthereof.

The equipment has female threads formed at its concave. Therefore, thepushing unit having male threads is certainly attached to the equipment.

Preferably, the main body is made of plastics.

The equipment is lightweight, and is convenient for use. In addition,there is no fear of metallic allergy because it is not made of metal.

ADVANTAGEOUS EFFECT OF THE INVENTION

By use of the percutaneously absorbable preparations embodying thepresent invention, even if the active substance is a percutaneouslypoorly absorbable drug, it is efficiently administered percutaneouslyinto the body.

By use of the sheet-like carrier embodying the present invention, thepercutaneously absorbable preparations are highly efficientlyadministered.

By use of the equipment embodying the invention, the needle-like orfilamentous shape percutaneously absorbable preparations are easilyadministered with high accuracy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view showing an embodiment of the needle-likepercutaneously absorbable preparations, and FIG. 1B is a perspectiveview which shows another embodiment of the needle-like percutaneouslyabsorbable preparations;

FIG. 2A is a perspective view showing a modified version of thepercutaneously absorbable preparations of FIG. 1A; FIG. 2B is aperspective view showing another modified version of the percutaneouslyabsorbable preparations of FIG. 1A; and FIG. 2C is a perspective viewshowing a modified version of the percutaneously absorbable preparationsof FIG. 1B.

FIG. 3 is a perspective view showing an embodiment of the filamentouspercutaneously absorbable preparations;

FIG. 4A is a perspective view showing an embodiment of thepercutaneously absorbable preparations having a secant in allsurroundings;

FIG. 4B is an enlarged sectional view of the part including the secantof FIG. 4A; and FIG. 4C is a perspective view showing an embodiment ofthe percutaneously absorbable preparations having a secant on a part ofthe surroundings;

FIG. 5 is an enlarged sectional view of a constricted part of thepercutaneously absorbable preparations;

FIG. 6 is a perspective view showing an embodiment of the percutaneouslyabsorbable preparations in the fifth aspect;

FIG. 7A is a side view schematically showing the initial stage ofmanufacturing process; FIG. 7B is a side view schematically showing themidway stage thereof; and FIG. 7C is a side view schematically showingthe final stage thereof;

FIG. 8A is a side view schematically showing the initial stage ofmanufacturing process; and FIG. 8B is a side view schematically showingthe final stage thereof;

FIG. 9 is an exploded perspective schematic view showing another exampleof the process of manufacturing the percutaneously absorbablepreparations of the invention;

FIG. 10 is a perspective view showing an embodiment of a sheet-likecarrier for holding the percutaneously absorbable preparations;

FIG. 11A is an exploded perspective view showing the first embodiment ofthe equipment of the invention; and FIG. 11B is a sectional perspectiveview showing the first embodiment thereof;

FIG. 12A is a schematic sectional view showing the pre-operation stateof the equipment of FIG. 11; and FIG. 12B is a schematic sectional viewshowing the post-operation state thereof;

FIG. 13A is a sectional view showing the second embodiment of theequipment of the invention; FIG. 13B is a sectional view showing thethird embodiment of the equipment of the invention;

FIG. 14 is a sectional view showing the fourth embodiment of theequipment of the invention;

FIG. 15 is an exploded perspective view showing the positional relationsbetween the pushing unit and the equipment in the fourth embodiment; and

FIG. 16A is a graph depicting the blood glucose level vs. time profilesafter the administration of the percutaneously absorbable preparationsin Example 20-1, 20-2 or 20-3; and FIG. 16 B is a graph depicting theblood glucose level vs. time profiles after the administration of thepercutaneously absorbable preparations in Example 20-4, 20-5 or 21.

DESCRIPTION OF THE NUMERALS

-   1, 1 a-1 q: percutaneously absorbable preparation-   21: percutaneously absorbable preparation-   31: percutaneously absorbable preparation-   41, 41 a-41 d: percutaneously absorbable preparation-   51: percutaneously absorbable preparation-   61: percutaneously absorbable preparation-   66: secant-   67: constricted line-   71: percutaneously absorbable preparation-   76 a, 76 b: secant-   81: percutaneously absorbable preparation-   91: base-   100: sheet-like carrier for holding the percutaneously absorbable    preparation-   102: supporting body-   110: percutaneously absorbable preparations holding equipment-   111: percutaneously absorbable preparation-   112: main body-   113: penetration hole-   115: bead (spacer)-   117: concave-   120: percutaneously absorbable preparations holding equipment-   121: percutaneously absorbable preparation-   130: percutaneously absorbable preparations holding equipment-   131: percutaneously absorbable preparation-   140: percutaneously absorbable preparations holding equipment-   147: concave

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Hereinafter, preferred embodiments of the present invention will bedescribed in detail.

All the percutaneously absorbable preparations of the present inventionhave a generally slender, pointed shape; herein, this shape beingreferred to as “needle-like or filamentous shape”. Examples of“needle-like” and “filamentous” percutaneously absorbable preparationsaccording to the present invention are illustrated by the accompanyingdrawings; FIGS. 1A and 1B show examples of percutaneously absorbablepreparations having a needle-like or filamentous shape. FIG. 1A is aperspective view showing an embodiment of the needle-like percutaneouslyabsorbable preparations. FIG. 1B is a perspective view which showsanother embodiment of the needle-like percutaneously absorbablepreparations. FIGS. 2A, 2B and 2C show modified versions ofpercutaneously absorbable preparations of FIGS. 1A and 1B. FIG. 2A is aperspective view showing a modified version of the percutaneouslyabsorbable preparations of FIG. 1A. FIG. 2B is a perspective viewshowing another modified version of the percutaneously absorbablepreparations of FIG. 1A. FIG. 2C is a perspective view showing amodified version of the percutaneously absorbable preparations of FIG.1B. FIG. 3 is a perspective view showing an embodiment of thefilamentous percutaneously absorbable preparations.

Percutaneously absorbable preparation 1 shown in FIG. 1A has asubstantially conical shape, and has a substantially circular pushingpart 2, a surface 3 consisting of a curved surface, and a pointed top 5.Percutaneously absorbable preparation 1 is inserted into the skin bypushing the pushing part 2 under the condition that the top 5 is kept incontact with the skin. The diameter D of the pushing part 2 is in arange of about 0.1-500 μm. The length H of the percutaneously absorbablepreparation 1 is in a range of about 0.5-1500 μm. The numerical valuesof 500 μm which is the maximum value of the diameter D and 1500 μm whichis the maximum value of the length are bigger than the diameter andlength of the usual microneedles. More specifically, percutaneouslyabsorbable preparation 1 includes not only conventional microneedles butalso larger size microneedles. On the other hand, percutaneouslyabsorbable preparation 11 shown in FIG. 1B has a substantiallyquadrilateral shape, and has a substantially square pushing part 12, asurface 13 consisting of four planes, and a pointed top 15. It isinserted into the skin by pushing the pushing part 12 under thecondition that the top 15 is in contact to the skin. Percutaneouslyabsorbable preparation 11 has the same size as percutaneously absorbablepreparation 1 shown in FIG. 1A. In the percutaneously absorbablepreparation 11 shown in FIG. 1B, though the pushing part 12 issubstantially square, another polygonal shape is accepted.Percutaneously absorbable preparation 21 shown in FIG. 2A is a modifiedversion of the percutaneously absorbable preparation 1 shown in FIG. 1A,and has a shape of a nail whose top is sharpened. As the percutaneouslyabsorbable preparation 1, percutaneously absorbable preparation 21 isinserted into the skin by pushing a pushing part 22 under the conditionthat a top 25 is in contact with the skin. Percutaneously absorbablepreparation 31 shown in FIG. 2B is another modified version of thepercutaneously absorbable preparation 1 and has a shape of thepercutaneously absorbable preparation 21 shown in FIG. 2A with atruncated cone placed on the pushing part 2. Percutaneously absorbablepreparation 31 is also inserted into the skin by pushing a pushing part32 under the condition that a top 35 is kept in contact with the skin.Percutaneously absorbable preparation 41 shown in FIG. 2C has a shape ofthe percutaneously absorbable preparation 21 shown in FIG. 1B with asquare pyramid placed on the pushing part 2. Percutaneously absorbablepreparation 41 is also inserted into the skin by pushing a pushing part42 under the condition that a top 45 is in contact with the skin. Asmentioned above, percutaneously absorbable preparations shown in FIGS.1A-1B and 2A-2C are all needle-like.

On the other hand, percutaneously absorbable preparation 51 shown inFIG. 3 is a filamentous solid preparation that has a shape as if acircular cylinder is diagonally cut. Percutaneously absorbablepreparation 51 has a pushing part 52 having a substantially circularshape, a surface 53 consisting of a curved surface, and a pointed top55. Percutaneously absorbable preparation 51 is inserted into the skinby pushing the pushing part 52 under the condition that the top 55 is incontact with the skin. The percutaneously absorbable preparation 51 hasthe same size as the percutaneously absorbable preparation 1 shown inFIG. 1A or the percutaneously absorbable preparation 11 as shown in FIG.1B. The expression “Filamentous” is replaced with the expression“Cylinder shape”.

All the percutaneously absorbable preparations of the present inventionare those having a base of water-soluble and biologically solublepolymer material, and an active substance held in the base, including,having a slender, pointed shape, such as a needle-like or filamentousshape, adapted for insertion into skin to percutaneously administer theactive substance into the body. Percutaneously absorbable preparationsof the present invention are chiefly composed of five aspects. A firstaspect relates to a conventional preparation. Second, third and fourthaspects relate to a sustained-release preparation. A fifth aspectrelates to a percutaneously absorbable preparation having at least twopercutaneously absorbable preparations linked in series.

In the first aspect of the percutaneously absorbable preparations ofthis invention, the base consists of at least one material selected fromthe group consisting of proteins, polysaccharides, polyvinyl alcohols,carboxyvinyl polymers and sodium polyacrylic acids. These polymermaterials each allow a stand-alone use or alternatively, a combinationuse with one or more other kinds. The method to hold the activesubstance in the base is not limited particularly, and various methodsare applied. For instance, the active substance is held by the base bymaintaining the active substance in the base as supramolecules. As otherexamples, the active substance is held in the base by adding the activesubstance to the dissolved base as suspension and thereafter solidified.

In the second aspect of the percutaneously absorbable preparations ofthis invention, a water-insoluble layer is formed on the surface, andthe active substance is released in a sustained-release fashion. In apreferred embodiment of this aspect, the water-insoluble layer is formedby a cross-linking reaction. As the method to make a cross-linkingreaction on the surface, for example, cross-linking reaction by treatingthe surface with glutaraldehyde is proposed. Precisely, percutaneouslyabsorbable preparations are soaked in glutaraldehyde solution. Asanother method to make a water-insoluble layer on the surface except across-linking reaction, the SiO thin film formation reaction by the gasphase reaction used in the semiconductor field is applied. As anotherexample, the method to make the surface insoluble by keeping under thecondition of the high temperature and high humidity is applicable whengelatin etc. is used as the base, though this method is used in thefield of capsule technology. Still another method is to soak thepercutaneously absorbable preparations in a saturated calcium chloridesolution. On the other hand, as the method to hold active substance inthe base, for example, the same method as described in the first aspectof the percutaneously absorbable preparations is applied.

In the third aspect of the percutaneously absorbable preparations ofthis invention, the base contains a porous compound. The activesubstance is held in the porous compound, and is released in asustained-release fashion. In a preferred embodiment of this aspect, theporous material is at least one material selected from the groupconsisting of calcium silicate, aluminum silicate, magnesium silicate,anhydrous silicate, porous calcium carbonate, porous calcium phosphateand porous silicon. These porous materials each allow a stand-alone useor alternatively, a combination use with one or more other kinds. Theseporous materials are commercially obtainable, and may be used withoutmodification. For instance, calcium silicate includes Florite (Tradename, Eisai Co., Ltd., Tokyo, Japan). Aluminum silicate and magnesiumsilicate includes Neusilin (Registered trademark, Fuji Chemical IndustryCo., Ltd., Toyama, Japan). Silicon dioxide includes Sylysia (Trade name,Fuji Silysia Co., Ltd., Aichi, Japan). Porous silicone includesBioSilicon (Trade name, pSivida Inc.). In addition, porous calciumcarbonate and porous calcium phosphate are obtainable from NationalInstitute for Materials, Japan, for instance. In the fourth aspect ofthe percutaneously absorbable preparations of this invention, the activesubstance is a long-acting material and is released in asustained-release fashion. In a preferred embodiment of this aspect, thelong-acting substance is long-acting type insulin or proteincross-linked with polyethylene glycol. Specific examples of thelong-acting insulin include middle-acting, long-acting andultra-long-acting insulins. Specific examples of the polyethylene glycolcross-linked protein include PEG-modified proteins such asPEG-interferon and PEG-erythropoietin.

In a preferred embodiment which is common to percutaneously absorbablepreparations of the above-mentioned second, third, and fourth aspects,the base consists of at least one material selected from the groupconsisting of proteins, polysaccharides, polyvinyl alcohols,carboxyvinyl polymers and sodium polyacrylic acids, as with the firstaspect. These macromolecules each allow a stand-alone use oralternatively, a combination use with one or more other kinds.

Preferred embodiments common to percutaneously absorbable preparationsof the above-mentioned four aspects are described below. In a preferredembodiment, the protein is at least one material selected from the groupconsisting of serum albumin, serum α-acid glycoprotein and gelatin.These proteins each allow a stand-alone use or alternatively, acombination use with one or more other kinds. Further, in a preferredembodiment, the polysaccharide is at least one material selected fromthe group consisting of glycogen, dextrin, dextran, dextran sulfate,sodium chondroitin sulfate, hydroxy propyl cellulose, alginic acid,agarose, chitin, chitosan, pullulan, and hyaluronic acid. Thesepolysaccharides each allow a stand-alone use or alternatively, acombination use with one or more other kinds. With respect to themolecular weight of the polysaccharides, for example, hyaluronic acidwith a molecular weight less than 1,200,000 are used, though lowmolecular weight hyaluronic acid less than about 90,000 are morepreferable. For dextran, for instance, dextran of which molecular weightis more than 50,000 is used. For dextran sulfate, dextran sulfate ofwhich molecular weight is about 500,000 is used. For hydroxypropylcellulose, low-substituted hydroxypropyl cellulose is preferably used.

In a preferred embodiment, the base contains an absorption ratecontroller for controlling the absorption rate of the active substance.In a further preferred embodiment, the absorption rate controller is anabsorption enhancer. In a still further preferred embodiment, theabsorption enhancer is a surfactant. Examples of the absorption enhancerinclude fatty acids such as caprylic acid, capric acid and itsderivatives, N-8-(2-hydroxybenzoyl)amino caprylic acid (SNAC), andsodium N-8-(2-hydroxybenzoyl)amino decanate (SNAD); glycyrrhizin;glycyrrhizinic acid; amino acid enamine derivatives such as ethylacetoacetate ethylenamine derivatives of phenylglycine; sodiumsalicylate and its derivatives; mixed micelles such as mixed micelles ofmono-olein and sodium glycocholate, and mixed micelles of mono-olein andsodium taurocholates; N-acylcollagen peptide; sodium acylamino acid;Plectranthus japonicus saponin; bile acids; chelate compounds such asEDTA; organic acids such as citric acids and tartaric acids. However,the absorption enhancer used in this embodiment is not limitedparticularly to these materials.

Surfactant as an absorption enhancer is used to increase thebioavailability and pharmacological activity of the active substance byaccelerating the dissolution rate of the active substance with lowsolubility in the surface and the dermis of the skin and by enhancingthe absorption of the active substance having low membrane permeabilitythrough the skin. Examples of the surfactant include glycerin fatty acidesters, commercially available as “Ryoto (registered trademark)Polyglyester” supplied by Mitsubishikagaku Foods Co. Ltd., such asdecaglycerine lauric acid esters L-7D and L-10D; decaglycerine myristicacid ester M-10D; decaglycerine stearic acid esters SWA-10D, SWA-15D,SWA-20D, S-24D and S-28D; decaglycerine oleic acid esters O-15D andO-50D; decaglycerine behenic acid esters B-70D and B-100D; decaglycerineerucic acid esters ER-30D and ER-60D; decaglecerine mixed fatty acidester LOP-120DP; polyglycerine stearic acid esters DS13W, DS3, HS11,HS9, TS4 and TS2; polyglycerine lauric acid ester DL15; andpolyglycerine oleic acid ester DO13.

Further, examples of the surfactant include stearoyl calcium lactate,sorbitan fatty acid ester, and propylene glycol fatty acid ester.Further, the examples include fatty acid sugar esters, commerciallyavailable as “Ryoto (registered trademark) Sugarester” supplied byMitsubishikagaku Foods Co. Ltd., such as S-1670, S-1570, S-1170, P-1570,P-1670, M-1695, O-1570, OWA 1570, and L-1695. Further, the examplesinclude DK esters F-160, F-140, and F-110 (Dai-ichi Kogyo Seiyaku Co.,Ltd.). Further, the examples include polysorbate 80, monooleic acid,polyethylene glycol monooleate, polyethylene glycol monostearate, andmiddle chain fatty acid triglycerides. Further, the examples include thesaturated fatty acids (C.sub 6 to C.sub 12) such as caproic acid,caprylic acid, capric acid, lauric acid, and lecithin.

Still further, liquid, semi-solid or solid surfactants except the abovementioned surfactants are used in this embodiment. These surfactants aredescribed separately with three categories, namely, non-ionicsurfactants, hydrophilic surfactants and ionic surfactants.

(a) Nonionic Surfactant

alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylenealkylphenols; polyethylene glycol fatty acids esters; polyethyleneglycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acidesters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerolfatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols;polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetableoils; reaction mixtures of polyols with at least one selected from thegroup consisting of fatty acids, glycerides, vegetable oils,hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers;sucroglycerides; and mixtures thereof.

(b) Hydrophilic Surfactants

PEG-10 laurate; PEG-12 laurate; PEG-20 laurate; PEG-32 laurate; PEG-32dilaurate; PEG-12 oleate; PEG-15 oleate; PEG-20 oleate; PEG-20 dioleate;PEG-32 oleate; PEG-200 oleate; PEG-400 oleate; PEG-15 stearate; PEG-32distearate; PEG-40 stearate; PEG-100 stearate; PEG-20 dilaurate; PEG-25glyceryl trioleate; PEG-32 dioleate; PEG-20 glyceryl laurate; PEG-30glyceryl laurate; PEG-20 glyceryl stearate; PEG-20 glyceryl oleate;PEG-30 glyceryl oleate; PEG-30 glyceryl laurate; PEG-40 glyceryllaurate; PEG-40 palm kernel oil; PEG-50 hydrogenated castor oil; PEG-40castor oil; PEG-35 castor oil; PEG-60 castor oil; PEG-40 hydrogenatedcastor oil; PEG-60 hydrogenated castor oil; PEG-60 corn oil; PEG-6caprate/caprylate glycerides; PEG-8 caprate/caprylate glycerides;polyglyceryl-10 laurate; PEG-30 cholesterol; PEG-25 phyto sterol; PEG-30soya sterol; PEG-20 trioleate; PEG-40 sorbitan oleate; PEG-80 sorbitanlaurate; polysorbate 20; polysorbate 80; POE-9 lauryl ether; POE-23lauryl ether; POE-10 oleyl ether; POE-20 oleyl ether; POE-20 stearylether; tocopheryl PEG-100 succinate; PEG-24 cholesterol; polyglyceryl-10oleate; Tween 40; Tween 60; sucrose monostearate; sucrose monolaurate;sucrose monopalmitate; PEG 10-100 nonyl phenol series; PEG 15-100 octylphenol series; and poloxamer; and mixtures thereof.

(c) Ionic Surfactants

alkyl ammonium salts; bile acids and salts; fusidic acid; fatty acidconjugates of amino acids, oligopeptides, or polypeptides; glycerideesters of polypeptides; acyl lactylates; mono- and diacetylated tartaricacid esters of mono- and diglycerides; succinylated monoglycerides;citric acid esters of mono- and diglycerides; alginate salts; propyleneglycol alginate; lecithins; hydrogenated lecithins; lysolecithin;hydrogenated lysolecithins; lysophospholipids; phospholipids; salts ofalkylsulfates; and salts of fatty acids.

Typical examples of the ionic surfactants include the following:phosphatidylcholine; phosphatidylethanolamine; phosphatidylglycerol;phosphatidic acid; phosphatidylserine; lysophosphatidylcholine;lysophosphatidylethanolamine; lysophosphatidylglycerol; lysophosphatidicacid; lysophosphatidylserine; PEG-phosphatidylethanolamine;PVP-phosphatidylethanolamine; lactylic esters of fatty acids;stearoyl-2-lactylate; succinylated monoglycerides; mono/diacetylatedtartaric acid esters of mono/diglycerides; citric acid esters ofmono/diglycerides; cholate; taurocholate; glycocholate; deoxycholate;taurodeoxycholate; chenodeoxycholate; glycodeoxycholate;glycochenodeoxycholate; taurochenodeoxycholate; ursodeoxycholate;lithocholate; tauroursodeoxycholate; glycoursodeoxycholate;cholylsarcosine; N-methyl taurocholate; caproate; caprylate; caprate;laurate; myristate; palmitate; oleate; ricinoleate; linoleate;linolenate; stearate; lauryl sulfate; teracecyl sulfate; docusate;lauroyl carnitines; palmitoyl carnitines; myristoyl carnitines; andsalts thereof; and mixtures of them including salts.

These surfactants also have a function of plasticizer. For instance,both absorption enhancing effect and stabilizing effect on the physicalstrength of percutaneously absorbable preparations are obtained byformulating polysorbate 80 into the base consisting of serum albumin.

In a preferred embodiment, the base contains a thread-reducing agent,thereby reducing the thread-forming property thereof. It has anadvantage in manufacturing, because the thread-forming property of thebase is well controlled in this embodiment. Examples of thethread-reducing agent include polyethylene glycol and L-glutamic acidL-lysine.

There is no limitation on the active substance in percutaneouslyabsorbable preparations of this invention. Examples of the activesubstances include drugs, physiologically active substances, cosmeticsand nutrients. When drugs are employed as an active substance,especially poorly absorbable drugs through percutaneous route are goodcandidate. Examples of category of the percutaneously poorly absorbabledrugs include peptides, proteins, nucleic acids, polysaccharides, othercompounds of which molecular weight is larger than 1,000, and vaccines.Examples of peptides and proteins include physiologically activepeptide/proteins such as insulin, calcitonin, erythropoietin (EPO),interferon, various interleukins, granulocyte colony-stimulating factors(G-CSF), vasopressin, desmopressin, urokinase, growth hormone,parathyroid hormone and grehelin. Examples of nucleic acids includevectors for gene therapy, anti-sense DNA, anti-sense RNA, and siRNA.Further, examples of vaccines include vaccines containing microorganismsuch as attenuated vaccines and inactivated vaccines, peptide vaccines,and nucleic acid vaccines such as DNA vaccines. Examples ofpolysaccharides include heparin and low molecular weight heparin.

Although there is no limitation in the content of the active substancein the percutaneously absorbable preparation of this invention, thecontent is generally 0.01-50 w/w %.

In a preferred embodiment, the base contains a stabilizer forstabilizing the active substance. Especially, when peptides or proteinsare employed as an active substance, it is preferable to containprotease inhibitor as a stabilizer. Examples of the protease inhibitorsinclude aprotinin and trypsin inhibitor. Further, when nucleic acids areemployed as an active substance, it is preferable to contain nucleaseinhibitor as a stabilizer.

In a further preferred embodiment, a moisture-proof layer is formed onthe surface of the percutaneously absorbable preparations. For example,the moisture-proof layer is prepared by coating the surface with polymersolution like polyethylene glycol (PEG), polyvinylpyrolidone andpolylactic acid, etc.

In all embodiments of the above-mentioned percutaneously absorbablepreparations, the surface is constricted or has a secant. Morespecifically, the dose of the administered active substance is madeaccurate by splitting along the constricted line or the secant afterinserting the percutaneously absorbable preparations into the skin. Theconstricted line or the secant may be provided to all or a part ofsurroundings of the preparation. FIGS. 4A, 4B and 4C show embodiments ofthe percutaneously absorbable preparations having a secant. FIG. 4A is aperspective view showing an embodiment of the percutaneously absorbablepreparations having a secant in all surroundings. FIG. 4B is an enlargedsectional view of the part including the secant of FIG. 4A. FIG. 4C is aperspective view showing an embodiment of the percutaneously absorbablepreparations having a secant on a part of the surroundings.Percutaneously absorbable preparation 61 shown in FIG. 4A is prepared byproviding preparation 1 shown in FIG. 1A with a secant. A secant 66 ismade on a surface 63 in all surroundings. As shown in FIG. 4B, thesecant 66 has a shape like a square groove. On the other hand,percutaneously absorbable preparation 71 as shown in FIG. 4C is preparedby providing preparation 1 shown in FIG. 1A with two secants. Morespecifically, secants 76 a and 76 b are made on mutually opposedportions on a surface 73. The shape of the secants 76 a and 76 b is thesame as the secant 61 shown in FIG. 4B. The secants 76 a and 76 b inFIG. 4A, FIG. 4B and FIG. 4C are drawn in an exaggerated manner by thesize and the size may be different from an actual size.

In the percutaneously absorbable preparation 61 shown in FIG. 4A, anexample of providing a constricted line instead of the secant 66 isshown in FIG. 5. FIG. 5 is an enlarged sectional view of a constrictedpart of the percutaneously absorbable preparations. As shown in FIG. 5,a constricted line 67 has a shape like a V-groove. Of course, as withthe percutaneously absorbable preparation 61 shown in FIG. 4C, theconstricted line 67 of FIG. 5 may be provided partially on the surface63 instead of all surroundings on the surface 63. The constricted line67 in FIG. 5 is drawn in an exaggerated manner by the size and the sizemay be different from an actual size.

According to the fifth aspect of the invention, percutaneouslyabsorbable preparations include at least two of percutaneouslyabsorbable preparations of the first, second, third or fourthembodiment, wherein the preparations are linked in series. FIG. 6 is aperspective view showing an embodiment of the percutaneously absorbablepreparations in the fifth aspect. In the percutaneously absorbablepreparation 81 shown in FIG. 6, several percutaneously absorbablepreparations shown in FIG. 2C are linked. More specifically, in thepercutaneously absorbable preparation 81 shown in FIG. 6, fourpercutaneously absorbable preparations 41 a-41 d are linked in series,resulting in providing four connected parts 48 a-48 c. When thepercutaneously absorbable preparation 81 is used, the part of thepercutaneously absorbable preparation 41 a is first inserted into theskin, and then cut at the connected part 48 a. Next, the part of thepercutaneously absorbable preparation 41 b is inserted into another parton the skin, and then cut at the connected part 48 b. Similarly, thesteps of “insertion into the skin” and “cut at a connected part” arerepeated. The four percutaneously absorbable preparations 41 a-41 d arecontinuously administered according to the percutaneously absorbablepreparation 81 in this embodiment.

Manufacturing methods of the percutaneously absorbable preparations ofthis invention will be described. Manufacturing methods of thepercutaneously absorbable preparations of this invention are not limitedparticularly, and various methods are applicable. In an example, a plateand a stick are used. FIG. 7 schematically shows the manufacturingprocess of the invented percutaneously absorbable preparations. FIG. 7Ais a side view schematically showing the initial stage of manufacturingprocess. FIG. 7B is a side view schematically showing the midway stagethereof. FIG. 7C is a side view schematically showing the final stagethereof. First of all, a base 91 that contains the active substance isput on a plate 92 that consists of fluorocarbon resin etc. In this case,it is preferable that the base consists of a thread-forming material soas to be a paste after dissolved with water. Next, the top of a glassstick 93 is in contact to the base 91 containing an active substance(FIG. 7A). The glass stick 93 is lifted at once, and the base 91containing an active substance and adhering to the top of the glassstick 93 is enlarged (FIG. 7B). In addition, the glass stick 93 islifted, and the base 91 containing an active substance is molded in aneedle-like or filamentous shape (FIG. 7C). Afterwards, percutaneouslyabsorbable preparation 1 having substantially the same shape as atruncated cone is manufactured by drying and hardening the needle-likeor filamentous shaped base 91 that contains an active substance. At thistime, a glass stick of which diameter is less than 5 mm is used, forinstance. Moreover, it does not limit to the glass stick, and awater-insoluble stick made of polypropylenes etc. is acceptable.

Although FIGS. 7A-7C show an example of the manufacturing method of onepercutaneously absorbable preparation, several percutaneously absorbablepreparations are made by the same principle. An example of such amanufacturing method is shown in FIGS. 8A and 8B. These figuresschematically show another method to make percutaneously absorbablepreparations of the invention. FIG. 8A is a side view schematicallyshowing the initial stage of manufacturing process. FIG. 8B is a sideview schematically showing the final stage thereof. As shown in FIG. 8A,a comb 95 having two or more projections instead of a stick is used inthis example. Then, five percutaneously absorbable preparations 1 a-1 eare made as shown in FIG. 8B through the same processes shown in FIGS.7A-7C. Of course, it is also possible to manufacture more percutaneouslyabsorbable preparations by increasing the number of projections of thecomb 95.

A method using a mold is also applicable as another manufacturing methodof percutaneously absorbable preparations of this invention. An exampleof the manufacturing process of the percutaneously absorbablepreparations using mold is shown in FIG. 9. FIG. 9 is an explodedperspective schematic view showing another example of the process ofmanufacturing the percutaneously absorbable preparations of theinvention. As shown in FIG. 9, a mold 97 is prepared by making conicholes 98 a, 98 b, and 98 c in front of the plate 92 that consists offluorocarbon resin etc. The base containing an active substance isfilled into these holes 98 a, 98 b, and 98 c, and is removed afterdrying or solidification. As a result, needle-like or filamentous shapepercutaneously absorbable preparations 1 f, 1 g and 1 h aremanufactured. If the base containing an active substance is a paste, itmay be dried or solidified after removed from the holes. The material ofthe plate 92 is not limited to be fluorocarbon resin. For example, aplate made of silicon resin or ABS resins are acceptable.

Methods to make a constricted line or a secant on the percutaneouslyabsorbable preparations of this invention are not limited particularly,and various methods are used. When a mold is used, a mold having a shapethat can provide a constricted line or a secant is employed. When aplate and a stick are used, the constricted line or the secant is made,for instance, by pressing a desired point before drying orsolidification process. Moreover, the constricted line or the secant isalso made by shaving the desired point after drying or solidificationprocess.

One aspect of a sheet-like carrier of the invention is a sheet-likecarrier for holding at least one of the percutaneously absorbablepreparations except the fifth aspect on at least one of the surfacesthereof, wherein the preparations held on the carrier are inserted intothe skin by pushing the carrier thereonto. An embodiment of thesheet-like carrier of this aspect is shown in FIG. 10. FIG. 10 is aperspective view showing an embodiment of a sheet-like carrier forholding the percutaneously absorbable preparations. More specifically, apercutaneously absorbable preparations holding sheet-like carrier 100 inthis embodiment consists of a sheet-like supporting body 102 and ninepercutaneously absorbable preparations 1 i-1 q, and the ninepercutaneously absorbable preparations 1 i-1 q are held on the one sideof the supporting body 102. The nine percutaneously absorbablepreparations 1 i-1 q are inserted into the skin by pushing thesheet-like carrier 100 onto the skin. After the sheet-like carrier 100is pushed onto the skin, the supporting body 102 may be kept contact tothe skin or only the supporting body 102 is removed from the skin.Although the sheet-like carrier 100 which holds nine percutaneouslyabsorbable preparations 1 i-1 q is shown in FIG. 10, a sheet-likecarrier of the present invention has no limitation on the number ofpercutaneously absorbable preparations, i.e. is allowed to hold onepreparation only or, on the other hand, to hold more than 10preparations. As the supporting body 102, conventional supporting bodiesfor use as a patch are used.

One aspect of equipment of the invention is equipment for holdingpercutaneously absorbable preparations including having a base ofwater-soluble and biologically soluble polymer material, an activesubstance held in the base, and having a slender, pointed shape, such asa needle-like or filamentous shape, adapted for insertion into skin topercutaneously administer the active substance into the body, theequipment including a main body having a penetration hole in and alongwhich the preparations are moved. Embodiments of the equipment in thisaspect are described with reference to FIGS. 11A-11B, 12A-12B and 13.FIGS. 11A and 11B show the first embodiment of the equipment of theinvention. FIG. 11A is an exploded perspective view showing the firstembodiment of the equipment of the invention. FIG. 11B is a sectionalperspective view showing the first embodiment thereof. FIGS. 12A and 12B schematically show the pre- and post-operation states of the equipmentof FIG. 11. FIG. 12A is a schematic sectional view showing thepre-operation state of the equipment of FIG. 11. FIG. 12B is a schematicsectional view showing the post-operation state thereof. FIGS. 13A and13B show other embodiments of the equipment of the invention. FIG. 13Ais a sectional view showing the second embodiment of the equipment ofthe invention. FIG. 13B is a sectional view showing the third embodimentof the equipment of the invention. FIG. 14 is a sectional view showingthe fourth embodiment of the equipment of the invention. FIG. 15 is anexploded perspective view showing the positional relations between thepushing unit and the equipment in the fourth embodiment.

As shown in FIG. 11A, percutaneously absorbable preparations holdingequipment 110 is composed of a main body 112 made of plastic, a bead 115(spacer) and a percutaneously absorbable preparation 111. A penetrationhole 113, which leads up and down, is installed in the main body 112,and the bead 115 and the percutaneously absorbable preparation 111 areheld in the penetration hole 113. The bead 115 and the percutaneouslyabsorbable preparation 111 move in and along the penetration hole 113.In addition, the bead 115 comes in contact with the percutaneouslyabsorbable preparation 111. The outer shape of the main body 112 is likea truncated cone. Its large diameter is about 20 mm, its small diameteris about 10 mm, and its height is about 20 mm. Percutaneously absorbablepreparation 111 is a preparation of either of the above described firstto fourth embodiments. Percutaneously absorbable preparation 111 has thesimilar shape as percutaneously absorbable preparation 21 shown in FIG.2A. Its diameter is about 0.2 mm, and its length is about 1.0 mm. Thebead 115 is a spheroidal member, and its diameter is almost the same asthe diameter of the percutaneously absorbable preparation 111. The bead115 is made of silicon, but glass, resin and metal etc. are alsoacceptable. In addition, the percutaneously absorbable preparationsholding equipment 110 has a skin contact surface 116 on the smalldiameter side. The skin contact surface 116 comes in contact with theskin when the percutaneously absorbable preparation 111 is used.Moreover, as shown in FIG. 11B, the main body 112 has a concave 117 towhich an end of the penetration hole 113 is open. The concave 117 ismade so that a pushing unit for pushing out the percutaneouslyabsorbable preparation 111 via the bead 115 is smoothly installed. InFIGS. 11A and 11B, to facilitate the understanding, the size of thepercutaneously absorbable preparation 111 and the penetration hole 113is drawn as an enlarged manner.

As shown in FIG. 12A, the bead 115 and the percutaneously absorbablepreparation 111 are stored in penetration hole 113 in the pre-operationstate of the equipment 110. When it is used, one side of the bead 115 ispushed from the side of the concave 117 of the percutaneously absorbablepreparations holding equipment 110. The bead 115 comes in contact withthe percutaneously absorbable preparation 111, and then, thepercutaneously absorbable preparation 111 is pushed via the bead 115. Inthis embodiment, one side of the bead 115 is pushed with a wire 118. Thewire 118 is made of stainless steel and has almost the same diameter asthe bead 115. As shown in FIG. 12B, the percutaneously absorbablepreparation 111 is completely pushed out by the wire 118 via the bead115 and is inserted into the skin 119. At this time, the wire 118 doesnot come in contact with the skin 119, because it works via the bead115. More specifically, the wire 118 is not polluted by the body fluidsecreted from the skin 119. In FIGS. 12A and 12B, to facilitate theunderstanding, the sizes of the percutaneously absorbable preparations111, the penetration hole 113, the bead 115, and the wire 118 are drawnas an enlarged manner.

In the percutaneously absorbable preparations holding equipment 110,another shape of the held percutaneously absorbable preparations isacceptable. Percutaneously absorbable preparations holding equipment 120as shown in FIG. 13A holds a percutaneously absorbable preparation 121having a filamentous shape. The percutaneously absorbable preparation121 has almost the similar shape as the percutaneously absorbablepreparation 51 of FIG. 3, and the size is almost the same as that of thepercutaneously absorbable preparation 111. On the other hand,percutaneously absorbable preparations holding equipment 130 shown inFIG. 13B holds a percutaneously absorbable preparation 131 having twopercutaneously absorbable preparations 41, shown in FIG. 2C, linked inseries. According to the percutaneously absorbable preparations holdingequipment 130, half of the percutaneously absorbable preparation 131 isrepeatedly administered at two times.

Female threads are formed in a concave 147 of percutaneously absorbablepreparations holding equipment 140 shown in FIG. 14. The percutaneouslyabsorbable preparations holding equipment 140 in this embodiment is usedby installing it to a pushing unit 141 shown in FIG. 15. The pushingunit 141 has the wire 118, and the wire 118 moves at a constant distanceby pushing a knock part 143. Moreover, the pushing unit 141 has a convexpart 142 that engages with the concave 147 of the percutaneouslyabsorbable preparations holding equipment 140. Male threads are made injust fit to the female threads formed in the concave 147 in the convexpart 142. As the pushing unit 141, for example, a mechanical pencil forwriting is applicable. More specifically, a mechanical pencil becomesuseful as the pushing unit 141 by using the wire 118 instead of an extralead, wherein the diameter of the wire 118 is the same as that of theextra lead. Moreover, the pushing unit 141 can be made by using themechanism of a knock-type ballpoint pen. In FIGS. 13A, 13B, 14 and 15,to facilitate the understanding, the sizes of the percutaneouslyabsorbable preparations 111, 121, 131, bead 115, and the wire 118 aredrawn as an enlarged manner.

As mentioned above, the percutaneously absorbable preparations holdingequipments 110, 120, 130 and 140 are mainly used as if it were acartridge of percutaneously absorbable preparations. A required numberof percutaneously absorbable preparations holding equipments 110, 120,130 and 140 are used by breaking the package when the equipments arepackaged piece by piece. Consequently, they are kept hygienic.

The following provides a more detailed explanation of the presentinvention through its examples, though this invention is not limitedwith these examples.

EXAMPLE 1

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing interferon (activesubstance) held in a base consisting of human serum albumin.

About 0.2 mL of distilled water was added to 150 mg of human serumalbumin (Sigma) to be dissolved. The solution was mixed well to give abase paste consisting of human serum albumin. To this base paste, μL ofinterferon alpha injection solution “Sumiferon” (Trademark, 6,000,000units/mL, Sumitomo pharmaceuticals), corresponding to 60,000 IU, wasadded and well mixed so that interferon was held in the base paste. Tothe base paste holding interferon, a top of a glass stick of whichdiameter was about 3 mm was attached. Thereafter, the top was graduallypulled apart so that the base paste attaching to the top has aneedle-like or filamentous shape. The needle-like or filamentous basepaste was solidified by drying at low temperature to give apercutaneously absorbable preparation having a needle-like orfilamentous shape.

Mice, about 30 g body weight, were fixed on an operating-table after theabdominal hair was shaved under anesthetized with pentobarbital. At thispoint, about 0.25 mL blood sample was at first collected from thejugular vein. Next, the percutaneously absorbable preparation made inthis example was inserted into the shaved abdominal skin of mice, andinterferon was administered percutaneously, wherein the dose ofinterferon was 10,000 IU/kg. Blood samples were collected from thejugular vein for 4 hr after administration. Serum sample was preparedfrom the obtained each blood sample, and interferon concentration ofeach serum sample was measured with ELISA. All data were calculated asthe mean +/−standard deviation (SD), wherein each group consists ofthree to four mice. The results are shown in Table 1. “ND” shows theconcentration below the detection limit (as the same as the followingtables). As a result, interferon concentration started to increase at 1hr after administration and showed its maximum concentration (22.9+/−7.9IU/mL) at 3 hr after administration. Therefore, it was shown thatinterferon was administered percutaneously with the percutaneouslyabsorbable preparation of this example.

TABLE 1 Elapsed time after administration (hr) before admin- istration 12 3 4 Interferon ND 5.8 ± 3.8 19.3 ± 8.5 22.9 ± 7.9 17.7 ± 3.4concentra- tion (IU/mL)

EXAMPLE 2

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing interferon (activesubstance) held in a base consisting of bovine serum α-acid glycoprotein(AAG).

About 50 μL of distilled water was added to 50 mg of bovine AAG (Sigma)to be dissolved. The solution was mixed well and water was evaporated togive a base paste consisting of AAG. To this base paste, 10 μL ofinterferon alpha injection solution “Sumiferon” (Trademark, 6,000,000units/mL, Sumitomo pharmaceuticals), corresponding to 60,000 IU, wasadded and well mixed so that interferon was held in the base paste. APercutaneously absorbable preparation having a needle-like orfilamentous shape was made with a glass stick in the same way as Example1.

EXAMPLE 3

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing FITC-labeled albumin(active substance) held in a base consisting of human serum albumin.FITC-labeled albumin was used as a model of vaccine.

FITC-labeled albumin was prepared by labeling human serum albumin withfluorescein isothiocyanate (FITC). On the other hand, about 0.2 mL ofdistilled water was added to 130 mg of human serum albumin (Sigma) to bedissolved. The solution was mixed well to give a base paste consistingof human serum albumin. To this base paste, 20 mg of FITC-labeledalbumin was added and well mixed, so that FITC-labeled albumin was heldin the base paste. To the base paste holding FITC-labeled albumin, a topof a polypropylene stick of which diameter was about 2 mm was attached.Thereafter, the top was gradually pulled apart so that the base pasteattaching to the top has a needle-like or filamentous shape. Theneedle-like or filamentous base paste was solidified by drying at lowtemperature to give a percutaneously absorbable preparation having aneedle-like or filamentous shape.

Mice, about 30 g body weight, were fixed on an operating-table after theabdominal hair was shaved under anesthetized with pentobarbital. At thispoint, about 0.25 mL blood was at first collected from the jugular vein.Next, five percutaneously absorbable preparations prepared in thisexample were inserted into the mice abdominal skin, and FITC-labeledalbumin was administered percutaneously. Whole blood was removed in thenext day and serum sample was prepared from the resulting blood. Eachserum sample was diluted at 20 times with distilled water and thefluorescent intensity was measured with spectrofluorometer with theexcitation wavelength of 490 nm and emission one of 510 nm. As a result,the serum sample obtained after administration showed 20 times strongerfluorescent intensity than that obtained before administration. Fromthese results, it was shown that FITC-labeled albumin as a model vaccinewas administered percutaneously.

EXAMPLE 4

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing insulin (activesubstance) held in a base consisting of sodium chondroitin sulfate C.

About 0.1 mL of distilled water was added to 200 mg of sodiumchondroitin sulfate C (Nacalai Tesque) to be dissolved. The solution wasmixed well under warm to give a base paste consisting of sodiumchondroitin sulfate C. After cooled to the room temperature, 10 μL ofsodium insulin solution (100 mg/mL, private processed product) was addedto this base paste and well mixed so that insulin was held in the basepaste. To the paste base holding insulin, a top of a polypropylene stickof which diameter was about 3 mm was attached. Thereafter, the top wasgradually pulled apart so that the base paste attaching to the top has aneedle-like or filamentous shape. In addition, a secant was made on thesurface of the needle-like or filamentous base paste with a wire ofwhich diameter was 20 μm. The needle-like or filamentous base paste withthe secant was solidified by drying at low temperature to give apercutaneously absorbable preparation having a needle-like orfilamentous shape.

The percutaneously absorbable preparation made in this example wasevaluated by means of hypoglycemic effect in mice. Mice, about 30 g bodyweight, were anesthetized by an injection of pentobarbital and werefixed on the operating-table after the hair of the abdomen was shaved.At this point, about 0.25 mL blood was at first collected from thejugular vein. Next, five percutaneously absorbable preparations(corresponding to 1.0 IU/kg) made in this example was inserted into theshaved abdomen, and insulin was administered percutaneously. Bloodsamples were collected from the jugular vein for 3 hr afteradministration. Serum samples were obtained from the obtained bloodsamples and glucose content in each serum sample was measured usingglucose assay kit (Glucose C II-Test kit, Wako Pure ChemicalIndustries). Each glucose level was shown as a relative value to thepre-dose level, 100%. All data were calculated as the mean +/−standarddeviation (SD), where each group consisting of three to four mice. Theresults are shown in Table 2. As a result, serum glucose level showedits minimum value within 1 hr after administration, and the effect ofinsulin was confirmed. From these results, it was shown that insulin wasadministered percutaneously by the percutaneously absorbable preparationof this example.

TABLE 2 Elapsed time after administration (hr) before administration 1 23 4 Glucose 100 28 ± 8 35 ± 11 62 ± 9 77 ± 8 level (%)

EXAMPLE 5

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing insulin (activesubstance) held in a base consisting of dextrin.

About 1 mL of distilled water was added to 2 g of dextrin (Wako PureChemical Industries) to be dissolved. The solution was mixed well withmotor and pestle to give a base paste consisting of dextrin. Ten μL ofsodium insulin solution (100 mg/mL, private processed product) was addedto 100 mg of this base paste and well mixed so that insulin was held inthe base paste. To the base paste holding insulin, a top of a glassstick of which diameter was about 3 mm was attached. Thereafter, the topwas gradually pulled apart so that the base paste attaching to the tophas a needle-like or filamentous shape. In addition, a secant was madeon the surface of the needle-like or filamentous base paste with a wireof which diameter was 20 μm. The needle-like or filamentous base pastewith the secant was solidified by drying at low temperature to give apercutaneously absorbable preparation having a needle-like orfilamentous shape.

Animal experiments using mice were performed in the same way as Example4. Table 3 shows the result. As a result, serum glucose level showed itsminimum value within 1 hr after administration, and the effect ofinsulin was confirmed. From these results, it was shown that insulin wasadministered percutaneously by the percutaneously absorbable preparationof this example.

TABLE 3 Elapsed time after administration (hr) before administration 1 23 4 Glucose level 100 21 ± 6 30 ± 7 56 ± 8 63 ± 7 (%)

EXAMPLE 6

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing erythropoietin(active substance) held in a base consisting of hydroxypropyl cellulose.

About 1 mL of distilled water was added to 2 g of hydroxypropylcellulose (L-HPC, Nippon Soda) to be dissolved. The solution was mixedwell with motor and pestle to give a base paste consisting ofhydroxypropyl cellulose. Ten μL of erythropoietin EPO injection “ESPO”(Trademark, 24,000 IU/mL, Kirin Breweries) was added to 100 mg of thisbase paste and well mixed so that erythropoietin was held in the basepaste. To the base paste holding erythropoietin, a top of a glass stickof which diameter was about 3 mm was attached. Thereafter, the top wasgradually pulled apart so that the base paste attaching to the top has aneedle-like or filamentous shape. The needle-like or filamentous basepaste was solidified by drying at low temperature to give apercutaneously absorbable preparation having a needle-like orfilamentous shape.

Mice, about 30 g body weight, were anesthetized by an injection ofpentobarbital and were fixed on the operating-table after the hair ofthe abdomen was shaved. The percutaneously absorbable preparation madein this example was inserted into the shaved abdomen, and erythropoietinwas administered percutaneously, wherein the dose was 100 IU/kg. Bloodsamples were collected from the jugular vein before and afteradministration for 5 hr. Serum samples were obtained from the obtainedblood samples and erythropoietin concentrations were measured by anELISA method. Table 4 shows the result. That is, erythropoietinconcentration started to increase at 1 hr after administration and keptrising until 5 hr. From these results, it was shown that erythropoietinwas administered percutaneously by the percutaneously absorbablepreparation of this example.

TABLE 4 Elapsed time after administration (hr) before admini- stration 12 3 4 5 Erythro- ND 8 ± 4 11 ± 5 18 ± 6 26 ± 5 36 ± 5 poietin concen-tration (IU/mL)

EXAMPLE 7

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing insulin (activesubstance) held in a base consisting of human serum albumin andhydroxypropyl cellulose.

About 0.2 mL of distilled water was added to 150 mg of human serumalbumin and 25 mg of hydroxypropyl cellulose (L-HPC, Nippon Soda) to bedissolved. The solution was mixed well to give a base paste consistingof human serum albumin and hydroxypropyl cellulose. Ten μL of sodiuminsulin solution (100 mg/mL, private processed product) was added to 100mg of this base paste and well mixed so that insulin was held in thebase paste. To the base paste holding insulin, a top of a polypropylenestick of which diameter was about 2 mm was attached. Thereafter, the topwas gradually pulled apart so that the base paste attaching to the tophas a needle-like or filamentous shape. In addition, a wire of 20 μm inthe diameter was attached to a part of the surface of the needle-like orfilamentous base, where the part is near the boundary between the baseand the top, and a constricted line for cut was made by rotating thewire. The needle-like or filamentous base paste with the constrictedline was solidified by drying at low temperature to give apercutaneously absorbable preparation having a needle-like orfilamentous shape.

EXAMPLE 8

This example illustrates a percutaneously absorbable preparation onwhich moisture-proof layer was formed with polyethylene glycol, whereinthe preparation has a needle-like and filamentous shape and containsinsulin (active substance) held in a base consisting of dextrin.

About 1.0 mL of distilled water was added to 2 g of dextrin (Wako PureChemical Industries) to be dissolved. The solution was mixed well withmotor and pestle to give a base paste consisting of dextrin. Ten μL ofsodium insulin solution (100 mg/mL, private processed product) was addedto 100 mg of this base paste and well mixed so that insulin was held inthe base paste. To the base paste holding insulin, a top of a glassstick of which diameter was about 3 mm was attached. Thereafter, the topwas gradually pulled apart so that the base paste attaching to the tophas a needle-like or filamentous shape. In addition, a wire of 20 μm inthe diameter was attached to a part of the surface of the needle-like orfilamentous base, where the part is near the boundary between the baseand the top, and a constricted line for cut was made by rotating thewire. The needle-like or filamentous base with the constricted line wassolidified by drying at low temperature to give a solid preparationhaving a needle-like or filamentous shape. On the other hand, methylenechloride solution containing 5% of polyethylene glycol 20000 (PEG20000,Nacalai Tesque) was made. The obtained solid preparation having aneedle-like or filamentous shape was soaked in this solution at theposition of the constricted line and coating on the surface of the solidpreparation was performed with PEG 20,000 after drying in air. Thus, apercutaneously absorbable preparation having a needle-like andfilamentous shape and having moisture-proof layer on its surface wasprepared.

EXAMPLE 9

This example illustrates a percutaneously absorbable preparation onwhich moisture-proof layer was formed with polyethylene glycol, whereinthe preparation has a needle-like and filamentous shape and containsinsulin (active substance) held in a base consisting of gelatin anddextrin.

About 3 μL of distilled water was added to 3 g of gelatin (Wako PureChemical Industries) and 0.8 g of dextrin (Wako Pure ChemicalIndustries) to be dissolved. The solution was mixed well at about 50° C.with motor and pestle to give a base paste consisting of gelatin anddextrin. Ten μL of sodium insulin solution (100 mg/mL, private processedproduct) was added to 100 mg of this base paste and well mixed so thatinsulin was held in the base paste. Thereafter, a needle-like andfilamentous solid preparation with a constricted line was obtained inthe same way as Example 8. In addition, the surface of the solidpreparation was coated with PEG 20000 in the same way as Example 8.Thus, a percutaneously absorbable preparation having a needle-like andfilamentous shape and having moisture-proof layer on its surface wasprepared.

EXAMPLE 10

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape, containing insulin (activesubstance) held in a base consisting of gelatin and dextrin, and furthercontaining soybean trypsin inhibitor (stabilizer).

About 3 mL of distilled water was added to 3 g of gelatin (Wako PureChemical Industries), 0.8 g of dextrin (Wako Pure Chemical Industries)and 1 mg of soybean trypsin inhibitor (Sigma) to be dissolved. Thesolution was mixed well at about 40° C. with motor and pestle to give abase paste consisting of gelatin and dextrin and containing soybeantrypsin inhibitor. Ten μL of sodium insulin solution (100 mg/mL, privateprocessed product) was added to 100 mg of this base paste and well mixedso that insulin was held in the base paste. On the other hand, a moldhaving a needle-like or filamentous shape was made by inserting a sewingneedle into a plate made of perfluoroalkoxy (PFA) resin with a hammer.The base paste holding insulin was introduced into this mold at 40° C.The introduced base paste was solidified by cooling after left at roomtemperature to give a solid preparation. The solid preparation wasremoved from the mold to give a percutaneously absorbable preparationhaving a needle-like or filamentous shape.

EXAMPLE 11

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape, containing low molecular weightheparin (active substance) held in a base consisting of sodiumchondroitin sulfate C, and further containing PEG 20,000(thread-reducing agent) and caprylic acid (absorption enhancer).

Fifty μL of 5% PEG 20,000 (Nacalai Tesque) solution was added to 100 mgof sodium chondroitin sulfate C (Nacalai Tesque) to be dissolved. Thesolution was mixed well with motor and pestle to give a base pasteconsisting of chondroitin sulfate C and containing PEG 20,000. To thisbase, 5 mg of low molecular weight heparin (Pamaparin) and 5 mg ofcapric acid (Wako Pure Chemical Industries) were added and well mixed sothat low molecular weight heparin and capric acid were held in the basepaste. To this base paste holding low molecular weight heparin andcapric acid, a top of a glass stick of which diameter was about 2 mm wasattached. Thereafter, the top was gradually pulled apart so that thebase paste attaching to the top has a needle-like or filamentous shape.In addition, a secant was made on the surface of the needle-like orfilamentous base paste with a wire of which diameter was 20 μm. Theneedle-like or filamentous base paste with the secant was solidified bydrying at low temperature to give a percutaneously absorbablepreparation having a needle-like or filamentous shape. Evaluation inanimal experiment using mice was performed as the same method as Example12 after-described.

EXAMPLE 12

This example illustrates a percutaneously absorbable preparation whichwas the same as that of Example 11 but does not have a secant.

A base paste consisting of sodium chondroitin sulfate C and containingPEG 20,000 was prepared in the same way as Example 11. Further, lowmolecular weight heparin and capric acid were held in the base paste inthe same way as Example 11. To this base paste holding low molecularweight heparin and capric acid, a top of a glass stick of which diameterwas about 3 mm was attached. Thereafter, the top was gradually pulledapart so that the base paste attaching to the top has a needle-like orfilamentous shape. The needle-like or filamentous base paste wassolidified by drying at low temperature to give a percutaneouslyabsorbable preparation having a needle-like or filamentous shape.

As a comparative example against Examples 11 and 12, a percutaneouslyabsorbable preparation which was the same as that of Example 11 but doesnot contain caprylic acid was made.

Mice, about 30 g body weight, were anesthetized by an injection ofpentobarbital and were fixed on the operating-table after the hair ofthe abdomen was shaved. Percutaneously absorbable preparations made inExample 11, Example 12 and comparative examples were inserted into theshaved abdominal skin respectively, and low molecular weight heparin wasadministered percutaneously. The dose was 100 IU/kg. Blood samples werecollected from the jugular vein for 4 hr after administration. Bloodsamples were obtained. Serum sample was prepared from the obtained eachblood sample, and heparin activity (anti-Xa activity) of each sample wasmeasured with Hemos IL™ Assay Kit (Instrumentation Laboratory, UnitedStates). Table 5 shows the result. With the percutaneously absorbablepreparations of Examples 11 and 12, anti-Xa activity started to increaseat 1 or 2 hr after administration and showed the maximum value at 3 hrafter administration. On the other hand, in the percutaneouslyabsorbable preparations of comparative example, anti-Xa activity was notdetected even at 4 hr after administration. Therefore, when the lowmolecular weight heparin is the active substance, it was shown that anabsorption enhancer such as caprylic acid was necessary.

TABLE 5 Elapsed time after administration (hr) before admini- stration 12 3 4 Anti-Xa Example 11 ND ND 0.13 ± 0.05 0.21 ± 0.08 0.19 ± 0.05activity Example 12 ND 0.12 ± 0.04 0.19 ± 0.07 0.20 ± 0.08 0.17 ± 0.07(IU/mL) Comparative ND ND ND ND ND example

EXAMPLE 13

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing interferon (activesubstance) held in a base consisting of glycogen.

About 1 mL of distilled water was added to 1 g of glycogen (NacalaiTesque) to be dissolved. The solution was mixed well under warm to givea base paste consisting of glycogen. To this base, 10 μL of interferonalpha injection solution “Sumiferon” (Trademark, 6,000,000 units/mL,Sumitomo Pharmaceuticals) corresponding to 60,000 IU was added and wellmixed so that interferon was held in the base paste. To this base pasteholding interferon, a top of a glass stick of which diameter was about 3mm was attached. Thereafter, the top was gradually pulled apart so thatthe base paste attaching to the top has a needle-like or filamentousshape. The needle-like or filamentous base paste was solidified bydrying at low temperature to give a percutaneously absorbablepreparation having a needle-like or filamentous shape.

EXAMPLE 14

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape, containing insulin (activesubstance) held in a base consisting of carboxyvinyl polymer, andfurther containing PEG 20,000 (thread-reducing agent).

Two mL of 1% PEG 20,000 (Nacalai Tesque) solution was added to 3 g ofcarboxyvinyl polymer (Nacalai Tesque) to be dissolved. The solution wasmixed well to give a base paste consisting of carboxyvinyl polymer andcontaining PEG 20,000. To 100 mg of this base paste, 10 μL of sodiuminsulin solution (100 mg/mL, private processed product) was added andwell mixed so that insulin was held in the base paste. To this basepaste, a top of a polypropylene stick of which diameter was about 3 mmwas attached. Thereafter, the top was gradually pulled apart so that thebase paste attaching to the top has a needle-like or filamentous shape.After a constricted line for cut was made in the same way as Example 8,the needle-like or filamentous base paste with the constricted line wassolidified by drying at low temperature to give a percutaneouslyabsorbable preparation having a needle-like or filamentous shape.

EXAMPLE 15

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing vitamin C (activesubstance) held in a base consisting of dextran and hyaluronic acid.

About 50 μL of distilled water was added to 80 mg of dextran (molecularweight 170,000-200,000, Nacalai Tesque), 2 mg of hyaluronic acid (meanmolecular weight 90,000, commodity code: FCH-SU, Kibun Food Chemifa Co.)and 5 mg of vitamin C (L-ascorbic acid, Wako Pure Chemical Industries)to be dissolved. The solution was mixed well to give a base pasteconsisting of dextran and hyaluronic acid and holding vitamin C. To thisbase paste holding vitamin C, a top of a glass stick of which diameterwas about 3 mm was attached. Thereafter, the top was gradually pulledapart so that the base paste attaching to the top has a needle-like orfilamentous shape. The needle-like or filamentous base paste wassolidified by drying at low temperature to give a percutaneouslyabsorbable preparation having a needle-like or filamentous shape.

EXAMPLE 16

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing vitamin C (activesubstance) held in a base consisting of pullulan and hyaluronic acid.

About 50 μL of distilled water was added to 50 mg of pullulan (commoditycode: PI-20, Hayashibara Shoji, Inc.), 1 mg of hyaluronic acid (meanmolecular weight 90,000, commodity code: FCH-SU, Kibun Food Chemifa Co.)and 2 mg of vitamin C (L-ascorbic acid, Wako Pure Chemical Industries)to be dissolved. The solution was mixed well to give a base pasteconsisting of pullulan and hyaluronic acid and holding vitamin C. Tothis base paste holding vitamin C, a top of a glass stick of whichdiameter was about 3 mm was attached. Thereafter, the top was graduallypulled apart so that the base paste attaching to the top has aneedle-like or filamentous shape. The needle-like or filamentous basepaste was solidified by drying at low temperature to give apercutaneously absorbable preparation having a needle-like orfilamentous shape.

EXAMPLE 17

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing low molecular weightheparin (active substance) held in a base consisting of human serumalbumin.

About 0.2 mL of distilled water was added to 150 mg of human serumalbumin to be dissolved. The solution was mixed well to give a basepaste consisting of human serum albumin. To this base paste, 5 mg of lowmolecular weight heparin (Parnaparin) was added and well mixed so thatlow molecular weight heparin was held in the base paste. To this basepaste, a top of a glass stick of which diameter was about 2 mm wasattached. Thereafter, the top was gradually pulled apart so that thebase paste attaching to the top has a needle-like or filamentous shape.The needle-like or filamentous base paste was solidified by drying inair to give a percutaneously absorbable preparation having a needle-likeor filamentous shape.

Mice, about 30 g body weight, were anesthetized by an injection ofpentobarbital and were fixed on the operating-table after the hair ofthe abdomen was shaved. A percutaneously absorbable preparation made inthis example was inserted into the shaved abdominal skin respectively,and low molecular weight heparin was administered percutaneously. Thedose was 100 IU/kg. Systemic blood samples were collected from thejugular vein for 6 hr after administration. Serum sample was preparedfrom the obtained each blood sample, and heparin activity (anti-Xaactivity) of each sample was measured with Hemos IL Assay Kit(Instrumentation Laboratory, United States). Table 6 shows the result.That is, serum anti-Xa activities were lower than its level ofquantitation, 0.1 IU/mL, before administration and at 1 hr afteradministration. Thereafter, anti-Xa activity increased gradually till 4hr. Therefore, it was shown that low molecular weight heparin wasadministered percutaneously with a percutaneously absorbable preparationof this example.

TABLE 6 Elapsed time after administration (hr) before adminis- tration 12 3 4 5 6 Anti-Xa ND ND 0.13 0.21 0.18 0.14 0.11 activity (IU/mL)

EXAMPLE 18

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing low molecular weightheparin (active substance) held in a base consisting of human serumalbumin, where the low molecular weight heparin was released with asustained-released manner.

According to the same method as Example 17, a solid preparation having aneedle-like or filamentous shape was obtained. On the other hand, 2 μLof 25% glutaraldehyde solution (Nacalai Tesque) was added to 10 mL ofethanol and was mixed well. To this mixture, the obtained solidpreparation was soaked for 5 min and cross-linking treatment wasperformed on its surface. The treated solid preparation was soaked inethanol and water for 30 sec, respectively and the surface was washed.The washed solid preparation was dried in air to give a percutaneouslyabsorbable preparation having a needle-like or filamentous shape.

With the percutaneously absorbable preparation made in this example,dissolution experiment was performed for 5 hr at 37° C. Ten mL ofdissolution test medium was prepared by diluting rat skin homogenate toten times with isotonic phosphate buffer (pH7.4). The anti-Xa activityof the dissolution test medium was measured by using the above-mentionedHemos IL Heparin Assay Kit. As a reference, the percutaneouslyabsorbable preparation made in Example 17 was used and the same studywas performed. Table 7 shows the result. That is, the anti-Xa activitywas not detected until 10 min after the start of the dissolutionexperiment. At 30 min after the start of the experiment, anti-Xaactivity was initially detected. Moreover, anti-Xa activity showed highvalues at 3 hr after the start of the experiment. On the other hand, inthe case of the percutaneously absorbable preparation made in Example17, anti-Xa activity started to be detected at 2 min after the start ofthe experiment. Thus, it was shown that low molecular weight heparin wasreleased from the percutaneously absorbable preparation made in thisexample with a sustained-release manner.

TABLE 7 Elapsed time after the start of dissolution experiment (min) 0 12 3 4 5 10 30 60 120 180 Anti-Xa activity Example ND ND 0.10 0.16 0.180.19 0.19 0.19 0.19 0.19 0.19 (IU/mL) 17 Example ND ND ND ND ND ND ND0.09 0.12 0.18 0.19 18

EXAMPLE 19

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing insulin (activesubstance) held in a base consisting of human serum albumin, where theinsulin was released with a sustained-released manner.

About 0.2 mL of distilled water was added to 150 mg of human serumalbumin to be dissolved. The solution was mixed well to give a basepaste consisting of human serum albumin. To 100 mg of this base, 10 μLof sodium insulin solution (100 mg/mL, private processed product) wasadded well mixed so that insulin was held in the base paste. To thisbase paste holding insulin, a top of a polypropylene stick of whichdiameter was about 2 mm was attached. Thereafter, the top was graduallypulled apart so that the base paste attaching to the top has aneedle-like or filamentous shape. Thereafter, glutaraldehyde treatmentwas performed in the same way as Example 18 to give a percutaneouslyabsorbable preparation having a needle-like or filamentous shape.

EXAMPLE 20

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing insulin (activesubstance) held in porous anhydrous silicate or porous calcium silicate(porous material), where the insulin was released with asustained-released manner.

Four kinds of porous anhydrous silicates (Trade names: Sylysia350,Sylysia440, Sylysia550 and Sylysia730 (Fuji Silysia Co., Ltd. Aichi,Japan)), and one kind of porous calcium silicate (Trade name: FloriteRE, Eisai) were examined as porous materials. In the following, exampleusing Sylysia 350 is named Example 20-1, example using Sylysia 440 isnamed Example 20-2, example using Sylysia 550 is named Example 20-3,example using Sylysia 730 is named Example 20-4 and example usingFlorite is named Example 20-5. On the other hand, bovine pancreaticinsulin (Wako Pure Chemical Industries) was dissolved with distilledwater to give 9.6 mg/mL insulin solution. To 15.9 mg of porous material,0.1 mL of the insulin solution was added. The solution was mixed welland dried to give insulin-adsorbed powder. On the other hand, about 0.15mL of distilled water was added to 317.5 mg of sodium chondroitinsulfate C (Nacalai Tesque) to be dissolved. The solution was mixed wellto give a base paste consisting of sodium chondroitin sulfate C. To thisbase paste, 16.86 mg of insulin-adsorbed powder was added and mixedwell. To this base paste containing porous material in which insulin washeld, a top of a glass stick of which diameter was about 3 mm wasattached. Thereafter, the top was gradually pulled apart so that thebase paste attaching to the top has a needle-like or filamentous shape.The needle-like or filamentous base paste was solidified by drying atlow temperature to give a percutaneously absorbable preparation having aneedle-like or filamentous shape, resulting in giving five kinds ofpercutaneously absorbable preparations. Evaluation in animal experimentusing mice was performed at the same time with Example 21after-described.

EXAMPLE 21

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape, containing middle-acting insulin(active substance) held in a base, and further containing L-glutamicacid-L-lysine (thread-reducing reagent), where the insulin was releasedwith a sustained-released manner.

About 0.45 mL of distilled water was added to 312.8 mg of sodiumchondroitin sulfate C (Nacalai Tesque) and 153.8 mg of L-glutamicacid-L-lysine (Ajinomoto) to be dissolved. The solution was mixed wellto give a base paste consisting of sodium chondroitin sulfate C. To thisbase paste, 0.167 IU of middle-acting insulin (Penfil N™, NovoNordisc)was added and well mixed so that middle-acting insulin was held in thebase paste. To this base paste holding middle-acting insulin, a top of aglass stick of which diameter was about 3 mm was attached. Thereafter,the top was gradually pulled apart so that the base paste attaching tothe top has a needle-like or filamentous shape. The needle-like orfilamentous base paste was solidified by drying at low temperature togive a percutaneously absorbable preparation having a needle-like orfilamentous shape.

The percutaneously absorbable preparations made in Examples 20 and 21were evaluated by means of hypoglycemic effect in mice. Morespecifically, mice, about 30 g body weight, were anesthetized by aninjection of pentobarbital and were fixed on the operating-table afterthe hair of the abdomen was shaved. Percutaneously absorbablepreparations made in Example 20 or 21 were inserted into the miceabdominal skin and insulin was administered percutaneously. The dose was2.5 IU/kg. Systemic blood was removed before and after administrationfor 24 hr. Serum samples were prepared from the obtained blood samplesand glucose concentration in each serum sample was measured usingglucose assay kit (Glucose C II-Test kit, Wako Pure ChemicalIndustries). Each glucose level was shown as a relative value to thepre-dose level, 100%. All data were calculated as the mean +/−standarddeviation (SD), wherein each group consists of three to four mice. Theresult is shown in FIGS. 16A and 16B. These figures show the time courseof blood glucose levels when percutaneously absorbable preparations ofExample 20 or 21 were inserted into the skin. FIG. 16A shows the timecourse of blood glucose levels when percutaneously absorbablepreparations of Example 20-1, 20-2 or 20-3 were inserted into the skin.FIG. 16B shows the time course of blood glucose levels whenpercutaneously absorbable preparations of Example 20-4, 20-5 or 21 wereinserted into the skin. The ordinate of FIGS. 16A and 16B is bloodglucose level and abscissa is the time. Control is the case wherepercutaneously absorbable preparations consisting of only base wereused. As a result, in five kinds of the percutaneously absorbablepreparations of Example 20, serum glucose levels decreased for 12 hrafter administration. Furthermore, in the percutaneously absorbablepreparations of Example 21, serum glucose levels decreased for 9 hrafter administration. From these results, it was shown that insulin wasadministered percutaneously with a sustained-release manner by thepercutaneously absorbable preparations of Example 20 or 21.

EXAMPLE 22

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing insulin (activesubstance) held in a base consisting of hyaluronic acid and dextran.

Thirty holes of about 1 mm in the diameter were made on an acrylic plateof about 2.0 mm in thickness. Sawing needles were penetrated to theseholes and were fixed where the needle top comes out of the surface of anacrylic plate about 200 μm. In addition, adhesive glue was injected fromthe inserted side of the needles and the needles were fixed to anacrylic plate. On the other hand, silicon resin was put in a petri dish.An acrylic plate with the above-mentioned needles was put on the siliconresin in the petri dish, and was left overnight. An acrylic plate withneedles was removed after the silicon resin was confirmed to be solid,and the mold made of the silicon resin was made.

To 2.4 mg of hyaluronic acid (mean molecular weight: 90,000, commoditycode: FCH-SU by Kibun Food Chemifa Co., Ltd.) and 2.4 mg of dextran(molecular weight: 50,000-70,000, Nacarai Tesque) to be dissolved, 2.5μL of distilled water was added. The solution was mixed well to give abase paste consisting of hyaluronic acid and dextran. To this basepaste, 0.2 mg of sodium insulin (private processed product) solution wasadded and well mixed so that insulin was held in the base paste. Thebase paste holding insulin was filled into the mold made of silicon. Thefilled base paste was solidified by drying at low temperature. Thesolidified base was removed from the mold to give a percutaneouslyabsorbable preparation having a needle-like or filamentous shape.

EXAMPLE 23

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing vitamin C (activesubstance) held in a base consisting of chitosan.

One hundred μL of acetic acid and about 1 mL of distilled water wereadded to 0.3 g of chitosan (Daikitosan VL, Dainichiseika Color &Chemicals Mfg. Co., Ltd.) to be dissolved. The solution was mixed wellunder stirring on a hot plate stirrer. Further, 1N NaOH solution wasadded so that pH of the solution was adjusted to about 6.5. Thissolution was stirred under warm air blow and water was evaporated togive a base paste consisting of chitosan. To this base paste, 5 mg ofvitamin C (L-ascorbic acid, Wako Pure Chemical Industries) was added andwell mixed so that vitamin C was held in the base paste. The base pasteholding vitamin C was filled into the mold in the same way as Example22. The filled base paste was solidified by drying at low temperature togive a percutaneously absorbable preparation having a needle-like orfilamentous shape.

EXAMPLE 24

This example illustrates a percutaneously absorbable preparation havinga needle-like and filamentous shape and containing insulin (activesubstance) held in a base consisting of sodium chondroitin sulfate C,where the insulin was released with a sustained-released manner.

To 4.8 mg of sodium chondroitin sulfate C (Nacalai Tesque) to bedissolved, 2.5 μL of distilled water was added. The solution was mixedwell to give a base paste consisting of sodium chondroitin sulfate C. Tothis base paste, 0.2 mg of sodium insulin (private processed product)was added and well mixed so that insulin was held in the base paste. Tothis base holding sodium chondroitin sulfate C, a top of a polypropylenetip was attached. Thereafter, the top was gradually pulled apart so thatthe base paste attaching to the top has a needle-like or filamentousshape. The needle-like or filamentous base paste was soaked in asaturated calcium chloride solution for 1 hr at 4° C. and was hardened.Through this process, water-insoluble layer was made on its surface. Thelayer was dried in air to give a percutaneously absorbable preparationhaving a needle-like or filamentous shape.

1. Percutaneously absorbable preparations having a base of water-solubleand biologically soluble polymer material, and an active substance heldin the base, comprising: having a slender, pointed shape, such as aneedle-like or filamentous shape, adapted for insertion into skin topercutaneously administer the active substance into the body, whereinthe polymer material is at least one material selected from the groupconsisting of proteins, polysaccharides, polyvinyl alcohols,carboxyvinyl polymers and sodium polyacrylic acids 2.-28. (canceled) 29.The percutaneously absorbable preparations of claim 1, wherein theprotein is at least one material selected from the group consisting ofserum albumin, serum α-acid glycoprotein and gelatin.
 30. Thepercutaneously absorbable preparations of claim 1, wherein thepolysaccharide is at least one material selected from the groupconsisting of glycogen, dextrin, dextran, dextran sulfate, sodiumchondroitin sulfate, hydroxy propyl cellulose, alginic acid, agarose,chitin, chitosan, pullulan and hyaluronic acid.
 31. The percutaneouslyabsorbable preparations of claim 1, wherein the base contains anabsorption rate controller for controlling the absorption rate of theactive substance.
 32. The percutaneously absorbable preparations ofclaim 31, wherein the absorption rate controller is an absorptionenhancer.
 33. The percutaneously absorbable preparations of claim 32,wherein the absorption enhancer is a surfactant.
 34. The percutaneouslyabsorbable preparations of claim 1, wherein the active substance is adrug.
 35. The percutaneously absorbable preparations of claim 34,wherein the drug falls in peptides, proteins, nucleic acids,polysaccharides or vaccine.
 36. The percutaneously absorbablepreparations of claim 1, wherein the base contains a stabilizer forstabilizing the active substance.
 37. The percutaneously absorbablepreparations of claim 1, further comprising a moisture-proof layerformed on the surface thereof.
 38. The percutaneously absorbablepreparations of claim 1, wherein the preparations are constricted orhave a secant in part on the surface thereof.
 39. The percutaneouslyabsorbable preparations of claim 1, wherein the preparations comprise atleast two of them linked in series.
 40. Percutaneously absorbablepreparations having a base of water-soluble and biologically solublepolymer material, and an active substance held in the base, comprising:having a slender, pointed shape, such as a needle-like or filamentousshape, adapted for insertion into skin to percutaneously administer theactive substance into the body, wherein the percutaneously absorbablepreparations have a water-insoluble layer formed on the surface thereof,and wherein the active substance is released in a sustained-releasefashion.
 41. The percutaneously absorbable preparations of claim 40,wherein the water-insoluble layer is formed by a cross-link reaction.42. The percutaneously absorbable preparations of claim 40, wherein thepolymer material is at least one material selected from the groupconsisting of proteins, polysaccharides, polyvinyl alcohols,carboxyvinyl polymers and sodium polyacrylic acids.
 43. Thepercutaneously absorbable preparations of claim 40, wherein thepreparations comprise at least two of them linked in series. 44.Percutaneously absorbable preparations having a base of water-solubleand biologically soluble polymer material, and an active substance heldin the base, comprising: having a slender, pointed shape, such as aneedle-like or filamentous shape, adapted for insertion into skin topercutaneously administer the active substance into the body, whereinthe base contains a porous compound, and wherein the active substance isheld in the porous compound and is released in a sustained-releasefashion.
 45. The percutaneously absorbable preparations of claim 44,wherein the porous material is at least one material selected from thegroup consisting of calcium silicate, aluminum silicate, magnesiumsilicate, anhydrous silicate, porous calcium carbonate, porous calciumphosphate and porous silicon.
 46. The percutaneously absorbablepreparations of claim 44, wherein the preparations comprise at least twoof them linked in series.
 47. Percutaneously absorbable preparationshaving a base of water-soluble and biologically soluble polymermaterial, and an active substance held in the base, comprising: having aslender, pointed shape, such as a needle-like or filamentous shape,adapted for insertion into skin to percutaneously administer the activesubstance into the body, wherein the active substance is a long-actingmaterial and is released in a sustained-release fashion.
 48. Thepercutaneously absorbable preparations of claim 47, wherein thelong-acting substance is long-acting type insulin or proteincross-linked with polyethylene glycol.
 49. The percutaneously absorbablepreparations of claim 47, wherein the preparations comprise at least twoof them linked in series.
 50. A sheet-like carrier for holding at leastone of the percutaneously absorbable preparations of claim 1 on at leastone of the surfaces thereof, wherein the preparations held on thecarrier are inserted into the skin by pushing the carrier thereonto. 51.A sheet-like carrier for holding at least one of the percutaneouslyabsorbable preparations of claim 40 on at least one of the surfacesthereof, wherein the preparations held on the carrier are inserted intothe skin by pushing the carrier thereonto.
 52. A sheet-like carrier forholding at least one of the percutaneously absorbable preparations ofclaim 44 on at least one of the surfaces thereof, wherein thepreparations held on the carrier are inserted into the skin by pushingthe carrier thereonto.
 53. A sheet-like carrier for holding at least oneof the percutaneously absorbable preparations of claim 47 on at leastone of the surfaces thereof, wherein the preparations held on thecarrier are inserted into the skin by pushing the carrier thereonto. 54.Equipment for holding percutaneously absorbable preparations comprisinghaving a base of water-soluble and biologically soluble polymermaterial, an active substance held in the base, and having a slender,pointed shape, such as a needle-like or filamentous shape, adapted forinsertion into skin to percutaneously administer the active substanceinto the body, the equipment comprising a main body having a penetrationhole in and along which the preparations are moved.
 55. Equipment forholding percutaneously absorbable preparations, the equipment comprisinga main body having a penetration hole in and along which thepreparations are moved, wherein the preparations fall in claim
 1. 56.Equipment for holding percutaneously absorbable preparations, theequipment comprising a main body having a penetration hole in and alongwhich the preparations are moved, wherein the preparations fall in claim40.
 57. Equipment for holding percutaneously absorbable preparations,the equipment comprising a main body having a penetration hole in andalong which the preparations are moved, wherein the preparations fall inclaim
 44. 58. Equipment for holding percutaneously absorbablepreparations, the equipment comprising a main body having a penetrationhole in and along which the preparations are moved, wherein thepreparations fall in claim
 47. 59. The equipment of claim 54, whereinthe penetration hole accommodates a spacer kept in contact with thepreparations held in the penetration hole, so that the spacer moves inand along the penetration hole while being kept in contact with thepreparations.
 60. The equipment of claim 54, wherein the main bodycomprises a concave to which the penetration hole is open.
 61. Theequipment of claim 60, wherein the concave comprises female threads cuton the inside wall thereof.
 62. The equipment of claim 54, wherein themain body is made of plastics.